8-Aminoguanine, a compound known since the turn of the century, has been reported to have PNP-activity by R. Parks, et. al., in Biochem. Pharm., 31 (2), 163 (1982).
9-(2-Furfuryl)guanine is a known compound described in J. Am. Chem. Soc., 81, 3046 (1959) having no disclosed utility. The present invention is related to novel purine derivatives not obvious to an ordinarily skilled artisan, particularly, 9-heteroaryl guanines as having PNP-inhibiting activity.
8-Amino-9-benzylguanine was discussed at the 16th Annual Graduate Student Meeting in Medicinal Chemistry, University of Michigan, Ann Arbor, Mich. However, the present compounds are not obvious from either the synthesis or biological activity of 8-amino-9-benzylquanine discussed.
With regard to various novel processes of the present invention Ji-Wang Chern, et al, describe "A Convenient Synthesis of 2-N-methoxycarbonylaminooxazolo[5,4-d]pyrimidines" in J. Het. Chem. 21, 1245-6 (1984). A similar synthesis is described by S. Ram, et al, in "A Synthesis of Carbamic Acid[Imidazo-Heteroaromatic]Methyl Ester Derivatives Using Methoxycarbonyl Isothiocynate," Heterocycles, Vol. 22, No. 8, 1984, pp 1789-90, in which methoxycarbonyl isothiocyanate is used in a one pot reagent for the ring closure of an o-diaminopyrimidine derivative to afford a purine derivative possessing the methoxycarbonylamino functionality at position eight. Further, the mechanism of these two synthesis is discussed by Ji-Wang Chern, et al, in "The Novel Ring Opening of an Oxazolo[5,4-d]Pyrimidine and Subsequent Rearrangement to Form an Imidazo[4,5-d]Pyrimidine," Heterocycles, Vol. 22, No. 11, 1984, pp 2439-2441. None of the disclosures include a disclosure of reaction conditions, or an Ar as a heteroaryl or substituted heteroaryl, substituent defined hereinafter for the compound of Formula I prepared by the novel processes of the present invention. That is, corresponding Ar groups as defined hereinafter for each of the novel intermediates III, II, and I to be heteroaryl or substituted heteroaryl are not included in the above references and furthermore are not obvious variants thereof.